1Division of Child and Adolescent Psychiatry, Department of Psychiatry, University of Colorado, Anshutz Medical Campus, Aurora

2Section on Bipolar Spectrum Disorders, Emotion and Development Branch, National Institute of Mental Health, National Institutes of Health, Department of Health and Human Services, Bethesda, Maryland

3Department of Psychology, University of Denver, Denver, Colorado

4Scientific and Statistical Computing Core, National Institute of Mental Health, National Institutes of Health, Department of Health and Human Services, Bethesda, Maryland

5currentlywith Department of Psychology and Neuroscience, University of North Carolina at Chapel Hill

6Section on Development and Affective Neuroscience, Emotion and Development Branch, National Institute of Mental Health, National Institutes of Health, Department of Health and Human Services, Bethesda, Maryland

FindingsIn this functional magnetic resonance imaging study of 115 participants, anxiety and irritability were jointly associated with the amygdala’s connectivity to regulatory regions in the prefrontal cortex during face emotion processing. In particular, when participants viewed very angry faces, high irritability and high anxiety were associated with increased amygdala–medial prefrontal cortex connectivity, while high irritability and low anxiety were associated with decreased connectivity in the same circuit.

MeaningAnxiety and irritability appear to interact to influence connectivity in the neural system mediating response to social threat.

Abstract

ImportancePsychiatric comorbidity complicates clinical care and confounds efforts to elucidate the pathophysiology of commonly occurring symptoms in youths. To our knowledge, few studies have simultaneously assessed the effect of 2 continuously distributed traits on brain-behavior relationships in children with psychopathology.

Design, Setting, and ParticipantsCross-sectional functional magnetic resonance imaging study in a large, well-characterized clinical sample at a research clinic at the National Institute of Mental Health. The referred sample included youths ages 8 to 17 years, 93 youths with anxiety, disruptive mood dysregulation, and/or attention-deficit/hyperactivity disorders and 22 healthy youths.

Main Outcomes and MeasuresThe child’s irritability and anxiety were rated by both parent and child on the Affective Reactivity Index and Screen for Child Anxiety Related Disorders, respectively. Using functional magnetic resonance imaging, neural response was measured across the brain during gender labeling of varying intensities of angry, happy, or fearful face emotions. In mixed-effects analyses, the shared and unique effects of irritability and anxiety were tested on amygdala functional connectivity and activation to face emotions.

ResultsThe mean (SD) age of participants was 13.2 (2.6) years; of the 115 included, 64 were male. Irritability and/or anxiety influenced amygdala connectivity to the prefrontal and temporal cortex. Specifically, irritability and anxiety jointly influenced left amygdala to left medial prefrontal cortex connectivity during face emotion viewing (F4,888 = 9.20; P < .001 for mixed model term). During viewing of intensely angry faces, decreased connectivity was associated with high levels of both anxiety and irritability, whereas increased connectivity was associated with high levels of anxiety but low levels of irritability (Wald χ21 = 21.3; P < .001 for contrast). Irritability was associated with differences in neural response to face emotions in several areas (F2, 888 ≥ 13.45; all P < .001). This primarily occurred in the ventral visual areas, with a positive association to angry and happy faces relative to fearful faces.

Conclusions and RelevanceThese data extend prior work conducted in youths with irritability or anxiety alone and suggest that research may miss important findings if the pathophysiology of irritability and anxiety are studied in isolation. Decreased amygdala–medial prefrontal cortex connectivity may mediate emotion dysregulation when very anxious and irritable youth process threat-related faces. Activation in the ventral visual circuitry suggests a mechanism through which signals of social approach (ie, happy and angry expressions) may capture attention in irritable youth.